Researchers in the lab of Yulia Nefedova, MD, Ph.D., at the Wistar Institute and collaborators at Jubilant Therapeutics Inc. have discovered a novel mechanism by which the protein arginine deiminase 4 (PAD4) in neutrophils promotes the progression of cancer. The article also revealed that inhibiting this function of PAD4 reduces primary tumor growth and metastasis and improves checkpoint inhibitor treatments. Jubilant Therapeutics Inc. is developing a novel small molecule PAD4 inhibitor that directly targets this mechanism. The findings appear in Research against cancera journal of the American Association for Cancer Research.
“The development of metastases remains one of the leading causes of cancer death. Tumor-associated neutrophils have long been implicated in cancer progression. Understanding the mechanisms by which these cells promote tumor growth and metastatic spread is critically important for the development of new treatments,” shares Yulia Nefedova, MD, Ph.D., Associate Professor, Immunology, Microenvironment Program and metastases, Ellen and Ronald Caplan Cancer Center of the Wistar Institute.
This research revealed the importance of the PAD4 protein in the migration of neutrophils, specialized white blood cells that serve as the first line of immune defense in the body, directly impacting both primary tumor growth and tumor spread. secondary malignancy. Both genetic deletion of PAD4 and pharmacological inhibition of PAD4 using the novel inhibitor from Jubilant Therapeutic Inc. significantly down-regulated the chemokine CXCR2, reduced immunosuppressive polymorphonuclear myeloid suppressor cells (PMN-MDSCs) at the at tumor and metastatic sites, activated T cells and synergized with the immune system blocking checkpoints.
All results indicate a potent antitumor effect of inhibition of PAD4 to target PMN-MDSCs in the tumor microenvironment. This discovery is being further investigated in the Nefedova laboratory at Wistar.
“These results highlight the potential of PAD4 inhibition as a novel cancer treatment approach, in addition to the previously established role of this pathway in autoimmune diseases,” said Luca Rastelli, Ph.D. , Chief Scientific Officer, Jubilant Therapeutics Inc. “We are developing several highly selective oral small molecule PAD4 inhibitors, with the goal of bringing this novel mechanism to the clinic as a potential therapeutic for tumor metastasis in colorectal and pancreatic cancers, patients with liver metastases as well as for acute and chronic autoimmune/inflammatory diseases.”
These discoveries were only made possible through collaboration between Wistar, a Philadelphia-based nonprofit biomedical research institute, and Jubilant Therapeutics Inc., a clinical-stage precision therapy company developing novel therapies to treat oncology and autoimmune diseases.
“Only by working together are we able to effectively translate our basic research discoveries into clinical realities,” said Heather Steinman, Ph.D., MBA, Vice President of Business Development, Wistar Institute and Director technology transfer executive.
Co-authors: Hui Deng, Cindy Lin, Laura Garcia-Gerique, Shuyu Fu, Zachary Cruz, Erin Bonner Matthew Rosenwasser, Sridharan Rajagopal, M. Naveen Sadhu, Chandru Gajendran, Mohd Zainuddin, Ramachandraiah Gosu, Dhanalakshmi Sivanandhan, Miriam A. Shelef , Brian Nam, Dan T. Vogl and Dmitry I. Gabrilovich.
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